Three male and two female contraceptive drug discovery projects will be pursued, using state-of-the-art methods such as high throughput screening, structure-based drug design, and hit-to-lead optinnization by medicinal chemistry: 1. H2-Gamendazole (H2-GMZ) and Analogues of Narciclasine (NAR) for Male Contraception: The hypothesis of this project is that H2-GMZ and other small molecules such as NAR can be developed as reversible non-hormonal anti-spermatogenic contraceptive agents that reversibly disrupt eEFIA-actin bundling in Sertoli cells. 2. Retinoic Acid Receptor Alpha (RARalpha) as a Target for Male Contraception: Knockout models of RARa (Rara') and animal experiments with a RAR pan-antagonist have validated RARalpha as a viable target for establishing reversible male infertility. The discovery of an alpha-selective RAR antagonist with good oral bioavailability is expected to provide a male contraceptive agent that has fewer unwanted side effects than existing pan-antagonists. 3. CATSPER as a Target for Male Contraception: The Cation channel of Sperm (CatSper) is involved in the regulation of intracellular calcium, an important component required for the initiation of sperm hypermotility during mammalian fertilization. Our working hypothesis is that inhibitors of CatSper will reduce sperm hypermotility by preventing Ca2+ influx and rendering sperm unable to successfully penetrate and fertilize the oocyte. 4. WEE2 Kinase as a Target for Female Contraception: Knockdown of WEE2 prevents fertilization of mature primate oocytes, indicating that WEE2 represents a promising target for the development of non-hormonal, gamete-specific contraceptive for women. 5. PDE3A as a Target for Female Contraception: The principal catabolic enzyme in the oocyte is phosphodiesterase 3A (PDE3A). Pharmacologic inhibitors of PDE3A block oocyte maturation in many species, including primates. These observations have led to the hypothesis that a selective PDE3A inhibitor could be developed as a female contraceptive agent.